tbuckley/cabot-search huggingface dataset:
Letter to the editor: Adipose lipolysis is important for ethanol to induce fatty liver in the NIAAA murine model of chronic and binge ethanol feeding
Authors: Wenhao Luo, Yawen Wang, Ye Li, Taiping Zhang
Journal: Hepatology (2022)

To the editor, We followed with interest the report by Mathur et al.1 on adipose lipolysis in mediating ethanol‐induced hepatic steatosis and lipid peroxidation, eventually leading to fatty liver. There are some disputes and defects in the experimental model. Firstly, the baseline of mice was different (male aged 8–10 weeks and female aged 10–12 weeks), and the alanine transaminase (ALT) and aspartate transaminase in the adipose‐specific Comparative Gene Identification‐58 knockout group were significantly higher than those in the wild‐type group. Meanwhile, some confounding factors affecting alcoholic fatty liver disease (AFLD) and hepatic steatosis were not included, such as initial hormone levels, body mass index, and primary disease.2 No clear statement about these factors between the groups was shown, and the samples are pretty small. Secondly, the feeding pattern in the article is unsuitable. In Figure S1A of Mathur et al., the feeding doses of the experimental group and the control group were different. Previous studies have shown that different feeding doses (50 g vs. 65 g) within a week can lead to differences in ALT, alkaline phosphatase, and insulin‐like growth factor‐1.3 In Figure S1C, almost all mice have significant weight loss after 15 days of feeding, regardless of feeding pattern. In a standard National Institute on Alcohol Abuse and Alcoholism model, no significant difference was found in the weight of mice through the trial.4 In addition, a recent study showed that an inadequate diet could significantly lead to fatty liver.5 This study is susceptible to selection bias because various factors may lead to fatty liver in mice. Thirdly, the diagnostic criteria for fatty liver are not given in this article. This study should provide a quantitative analysis of pathological hepatocyte sections for diagnosing fatty liver. In conclusion, this study provides a new reference for adipose lipolysis playing a vital role in fatty liver, but AFLD may not be relevant.
Primers matter: Influence of the primer selection on human fungal detection using high throughput sequencing
Authors: Crispin Wiesmann, Konrad Lehr, Juozas Kupcinskas, Ramiro Vilchez-Vargas, Alexander Link
Journal: Gut Microbes (2022)

Microbiota research has received an increasing attention for its role in disease development and fungi are considered as one of the key players in the microbial niche. Various sequencing approaches have been applied to uncover the role of fungal community in health and disease; however, little is known on the performance of various primers and comparability between the studies. Motivated by the recent publications, we performed a systematic comparison of the 18S and ITS regions to identify the impact of various primers on the sequencing results. Using four pairs of primers extensively used in literature, fungal community was retrieve from 25 fecal samples, and applying high throughput sequencing; and the results were compared in order to select the most suitable primers for fungal detection in human fecal samples. Considering the high variability between samples, primers described in the Earth microbiome project detected the broadest fungal spectrum suggesting its superior performance in mycobiome research.
The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma
Authors: Romain Donne, Amaia Lujambio
Journal: Hepatology (2022)

The liver is the sixth most common site of primary cancer in humans and the fourth leading cause of cancer‐related death in the world. Hepatocellular carcinoma (HCC) accounts for 90% of liver cancers. HCC is a prevalent disease with a progression that is modulated by the immune system. Half of the patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib, as a first‐line therapy. In the last few years, immune‐checkpoint inhibitors (ICIs) have revolutionized cancer therapy and have gained an increased interest in the treatment of HCC. In 2020, the combination of atezolizumab (anti‐programmed death‐ligand 1) and bevacizumab (anti–vascular endothelial growth factor) improved overall survival over sorafenib, resulting in Food and Drug Administration (FDA) approval as a first‐line treatment for patients with advanced HCC. Despite these major advances, a better molecular and cellular characterization of the tumor microenvironment is still needed because it has a crucial role in the development and progression of HCC. Inflamed (hot) and noninflamed (cold) HCC tumors and genomic signatures have been associated with response to ICIs. However, there are no additional biomarkers to guide clinical decision‐making. Other immune‐targeting strategies, such as adoptive T‐cell transfer, vaccination, and virotherapy, are currently under development. This review provides an overview on the HCC immune microenvironment, different cellular players, current available immunotherapies, and potential immunotherapy modalities.
The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation
Authors: Ruth Meier, Gabriele Greve, Dennis Zimmer, Helena Bresser, Bettina Berberich, Ralitsa Langova, Julia Stomper, Anne Rubarth, Lars Feuerbach, Daniel B. Lipka, Joschka Hey, Björn Grüning, Benedikt Brors, Justus Duyster, Christoph Plass, Heiko Becker, Michael Lübbert
Journal: Blood Cancer Journal (2022)

Abstract The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all- trans retinoic acid (ATRA) resulted in an improved response rate and longer overall survival in a randomized phase II trial (DECIDER; NCT00867672). The molecular mechanisms governing this in vivo synergism are unclear. We now demonstrate cooperative antileukemic effects of DAC and ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, derepression of &gt;1200 commonly regulated transcripts following the dual treatment was observed. Overall chromatin accessibility (interrogated by ATAC-seq) and, in particular, at motifs of retinoic acid response elements were affected by both single-agent DAC and ATRA, and enhanced by the dual treatment. Cooperativity regarding transcriptional induction and chromatin remodeling was demonstrated by interrogating the HIC1 , CYP26A1 , GBP4 , and LYZ genes, in vivo gene derepression by expression studies on peripheral blood blasts from AML patients receiving DAC + ATRA. The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53 ) than MOLM-13 (intact TP53 ), resulting in a “viral mimicry” response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA.
Outcomes of patients with stage I–II Hodgkin lymphoma who had uniform pre-treatment staging with PET/CT and treatment with limited field radiation therapy after chemotherapy
Authors: Kelsey M. Frechette, Scott C. Lester, Kekoa Taparra, William G. Breen, James A. Martenson, Bradford S. Hoppe, Jennifer L. Peterson, William G. Rule, Scott L. Stafford, Bradley J. Stish, Thomas M. Habermann, Jason R. Young, William S. Harmsen, Nadia N. Laack
Journal: Blood Cancer Journal (2022)

Outcomes of patients with stage I-II Hodgkin lymphoma who had uniform
Myeloma precursor disease (MGUS) among rescue and recovery workers exposed to the World Trade Center disaster
Authors: Rachel Zeig-Owens, David G. Goldfarb, Benjamin J. Luft, Xiaohua Yang, Kazunori Murata, Lakshmi Ramanathan, Katie Thoren, Sital Doddi, Urvi A. Shah, Alexandra K. Mueller, Charles B. Hall, Orsi Giricz, Amit Verma, David J. Prezant, Ola Landgren
Journal: Blood Cancer Journal (2022)

Abstract An elevated risk of myeloma precursor disease, monoclonal gammopathy of undetermined significance (MGUS), was identified among Fire Department of the City of New York (FDNY) World Trade Center (WTC)-exposed firefighters. Further investigation was needed to determine if these findings were reproducible in a more heterogeneous WTC-exposed rescue/recovery workers cohort, the Stony Brook University-General Responder Cohort GRC (SBU-GRC). MGUS risk was compared between the cohorts and to published general population estimates from Olmsted County, MN, USA. In this observational seroprevalence study, odds ratios (OR) and age-standardized risk ratios (RR) of MGUS (M-spike and light-chain-MGUS combined), M-spike, and light-chain-MGUS were estimated using logistic regression. Age-standardized prevalences were calculated for white males aged 50–79; RRs were estimated by comparing risk in the WTC-exposed cohort with the Olmsted County screened cohort. SBU-GRC had elevated odds of MGUS compared with FDNY (OR = 1.38; 95%CI = 1.00–1.89). The age-standardized prevalence of MGUS was 9.0/100 persons (95%CI = 7.5–10.6), over two-fold higher than the general population (RR = 2.08; 95%CI = 1.72–2.51); the age-standardized prevalence of light-chain-MGUS was 3.5-fold higher (RR = 3.54; 95%CI = 2.52–4.97). This study adds to mounting evidence supporting an association between WTC/environmental exposures and MGUS among rescue/recovery workers. Access to MGUS screenings for the entire WTC-exposed cohort could allow for treatment interventions that improve survival.
Attacking the public health crisis of hepatocellular carcinoma at its roots
Authors: Hannah M. Lee, Steven D. Lidofsky, Tamar H. Taddei, Lisa J. Townshend‐Bulson
Journal: Hepatology (2022)

As the third most common cause of cancer‐related death worldwide with significant mortality rates in the United States, hepatocellular carcinoma has strong association with cirrhosis and chronic hepatitis B virus (HBV) with a growing at‐risk population from the rise in chronic liver disease from alcohol use and nonalcoholic fatty liver disease. Despite this, progress in identifying at‐risk individuals and early detection of HCC in these populations have lagged behind treatment advances.The lack of consensus may undermine widespread adoption of surveillance programs, thus preventing HCC detection at a curable stage. This public policy corner piece focuses on opportunities for prevention of HCC by focusing on its principal risk factors: viral hepatitis, NAFLD, and alcohol‐related liver disease, and three key action points to reverse the course of this public health crisis: 1) Awareness and education; 2) Screening and diagnosis, and 3) Partnerships and advocacy.
Natural history of human Monkeypox in individuals attending a sexual health clinic in Milan, Italy
Authors: Davide Moschese, Giacomo Pozza, Andrea Giacomelli, Davide Mileto, Maria Vittoria Cossu, Martina Beltrami, Alberto Rizzo, Maria Rita Gismondo, Giuliano Rizzardini, Spinello Antinori
Journal: Journal of Infection (2022)
Re-emergence of Severe Acute Diarrhea Syndrome Coronavirus (SADS-CoV) in Guangxi, China, 2021
Authors: Yankuo Sun, Jiabao Xing, Zhi-Ying Xu, Han Gao, Si-Jia Xu, Jing Liu, Di-Hua Zhu, Yi-Fan Guo, Bin-Shuo Yang, Xiong-Nan Chen, Ze-Zhong Zheng, Heng Wang, Gong Lang, Edward C Holmes, Gui-Hong Zhang
Journal: Journal of Infection (2022)
PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2
Authors: Michelle A. Baum, Craig Langman, Pierre Cochat, John C. Lieske, Shabbir H. Moochhala, Shuzo Hamamoto, Hiroyuki Satoh, Chebl Mourani, Gema Ariceta, Armando Torres, Martin Wolley, Vladimir Belostotsky, Thomas A. Forbes, Jaap Groothoff, Wesley Hayes, Burkhard Tönshoff, Tatsuya Takayama, Ralf Rosskamp, Kerry Russell, Jing Zhou, Aniruddha Amrite, Bernd Hoppe
Journal: Kidney International (2022)
Performance of American Gastroenterological Association Clinical Care Pathway for the risk stratification of patients with nonalcoholic fatty liver disease in the US population
Authors: Prowpanga Udompap, Terry M. Therneau, Rachel E. Canning, Joanne T. Benson, Alina M. Allen
Journal: Hepatology (2022)

Background and aims: The American Gastroenterological Association (AGA) recently launched the Clinical Care Pathway for the Risk Stratification and Management of Patients with NAFLD to identify adults with significant fibrosis. We aimed to examine this pathway’s performance in the US population. Approach and Results: Using the 2017–2018 National Health and Nutrition Examination Survey data, we identified participants aged ≥18 with available Fibrosis‐4 (FIB‐4) score and liver stiffness measurement (LSM) in the absence of other liver diseases. Based on the AGA clinical pathway, FIB‐4 &lt; 1.3 and LSM &lt; 8 kilopascals (kPa) by vibration‐controlled transient elastography (VCTE) are associated with low risk of significant fibrosis. Using these cutoffs, we examined the pathway performance using negative predictive value (NPV) and positive predictive value (PPV) and explored alternative risk‐stratification strategies. There were 2322 participants with available data (projected to 94.2 million US adults). The NPV of LSM ≥ 8 kPa among those with FIB‐4 &lt; 1.3 was 90%, whereas the PPV among those with FIB‐4 1.3–2.67 was 13%. As diabetes was a strong predictor of fibrosis, we propose a simple, alternative strategy to eliminate the indeterminate FIB‐4 range and perform VCTE in those with FIB‐4 ≥ 1.3 and diabetes. This strategy would decrease the number of VCTEs from 14.5 to 4.9 million and increase PPV from 13% to 33% without compromising the NPV among those who did not undergo VCTE. Conclusion: The implementation of the current AGA clinical pathway would lead to overutilization of VCTE. An alternative strategy using FIB‐4 ≥ 1.3 and diabetes to select adults undergoing second‐line testing will improve this pathway’s performance and minimize unnecessary VCTEs.
AIF1+CSF1R+ MSCs, induced by TNF‐α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis
Authors: Chen Zong, Yan Meng, Fei Ye, Xue Yang, Rong Li, Jinghua Jiang, Qiudong Zhao, Lu Gao, Zhipeng Han, Lixin Wei
Journal: Hepatology (2022)

Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure.Using single-cell RNA sequencing, we identified a distinct inflammation-associated subset of MSCs, namely AIF1 + CSF1R + MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF-α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad-Sirt1-MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C-C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad-Sirt1-MSCs attenuated the promotive effect of Ad-Sirt1-MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up-regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs.Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.
Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial
Authors: Sebastian Bauer, Robin L. Jones, Jean-Yves Blay, Hans Gelderblom, Suzanne George, Patrick Schöffski, Margaret von Mehren, John R. Zalcberg, Yoon-Koo Kang, Albiruni Abdul Razak, Jonathan Trent, Steven Attia, Axel Le Cesne, Ying Su, Julie Meade, Tao Wang, Matthew L. Sherman, Rodrigo Ruiz-Soto, Michael C. Heinrich
Journal: Journal of Clinical Oncology (2022)

PURPOSE Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501 ). PATIENTS AND METHODS Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/ platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib ( KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P &lt; .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.
Right Ventricular Longitudinal Contractility Mismatch
Authors: Simone Frea, Pier Paolo Bocchino, Filippo Angelini, Carol Gravinese, Guglielmo Gallone, Angelica Clivio, Elisabetta Toso, Carla Giustetto, Gaetano Maria de Ferrari
Journal: JACC. Cardiovascular imaging (2022)
Health disparities in chronic liver disease
Authors: Ani Kardashian, Marina Serper, Norah Terrault, Lauren D. Nephew
Journal: Hepatology (2022)

The syndemic of hazardous alcohol consumption, opioid use, and obesity has led to important changes in liver disease epidemiology that have exacerbated health disparities. Health disparities occur when plausibly avoidable health differences are experienced by socially disadvantaged populations. Highlighting health disparities, their sources, and consequences in chronic liver disease is fundamental to improving liver health outcomes. There have been large increases in alcohol use disorder in women, racial and ethnic minorities, and those experiencing poverty in the context of poor access to alcohol treatment, leading to increasing rates of alcohol-associated liver diseases. Rising rates of NAFLD and associated fibrosis have been observed in Hispanic persons, women aged > 50, and individuals experiencing food insecurity. Access to viral hepatitis screening and linkage to treatment are suboptimal for racial and ethnic minorities and individuals who are uninsured or underinsured, resulting in greater liver-related mortality and later-stage diagnoses of HCC. Data from more diverse cohorts on autoimmune and cholestatic liver diseases are lacking, supporting the need to study the contemporary epidemiology of these disorders in greater detail. Herein, we review the existing literature on racial and ethnic, gender, and socioeconomic disparities in chronic liver diseases using a social determinants of health framework to better understand how social and structural factors cause health disparities and affect chronic liver disease outcomes. We also propose potential solutions to eliminate disparities, outlining health-policy, health-system, community, and individual solutions to promote equity and improve health outcomes.
Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex
Authors: Martina Patone, Xue W. Mei, Lahiru Handunnetthi, Sharon Dixon, Francesco Zaccardi, Manu Shankar-Hari, Peter Watkinson, Kamlesh Khunti, Anthony Harnden, Carol A.C. Coupland, Keith M. Channon, Nicholas L. Mills, Aziz Sheikh, Julia Hippisley-Cox
Journal: Circulation (2022)

Background: Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain. Methods: A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test. Results: In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09–1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24–1.85]; 1.57 [95% CI, 1.28–1.92], and 1.72 [95% CI, 1.33–2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64–14.36] and 5.97 [95% CI, 4.54–7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25–19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25–5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91–99] versus 16 [95% CI, 12–18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1–9] versus 8 [95% CI, 6–8]). Conclusions: Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.